Human immunodeficiency virus type 1 infection of CD4+ T cells down-regulates the expression of CD28: effect on T cell activation and cytokine production.
ABSTRACT Infection with human immunodeficiency virus type 1 (HIV-1) results in dysregulation of normal T cell function. To study the effects of HIV-1 at the cellular level, primary T cell lines were generated by alloantigen stimulation of CD4+ T cells collected from peripheral blood of HIV-1-infected donors. Using Epstein-Barr virus-infected B lymphocytes (EBV-LCL) as a source of alloantigen, the T cell lines were expanded in vitro for 7 weeks. Uninfected T cell lines were cultured in parallel. Virus was inducible from the infected lines with stimulation, and complete infection was achieved after 4-7 weeks depending on the line. The down-modulation of CD28 expression correlated with virus replication and spread. Furthermore, CD28 mRNA was not inducible in the infected lines after stimulation with alloantigen. Loss of CD28 correlated with reduced responsiveness to costimulation with a monoclonal antibody to CD28 following similar engagement of the CD3 protein. In contrast, activation with alloantigen was not affected. HIV-1 infection and down-modulation of CD28 did not alter the relative levels of IL-2, IFN-gamma, and IL-4 mRNA. Production of the various cytokine mRNAs following alloantigen stimulation was inhibited by CTLA4Ig and thus remained under the regulation of CD80 and CD86 expressed on the EBV-LCL. Taken together, our data suggest that dysregulation of normal T cell function associated with HIV-1 infection may result in part form the loss of CD28 expression.
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ABSTRACT: In 42 HIV-infected children, 8-10 years old, belonging to the category A state of infection, combined antiretroviral therapy (cART) was applied, consisting of AZT, ddC and Saquinavir. At 6 and 12 weeks following the start of cART, the efficacy of treatment was assessed, both by means of current parameters (blood CD4+ cell levels, virus load) and by measuring the intracellular synthesis of some Th1 (interleukin (IL)-2, interferon-gamma) and Th2 (IL-4, IL-10) cytokines, in CD4+ lymphocytes, respectively. Before cART, low values of blood CD4+ cell counts and a mean of about 8000 virus RNA copies ml(-1) of serum were detected, and in addition decreased levels of production of both intracellular Th1 cytokines, associated with increased levels of one of the Th2 cytokines (IL-10), but not of the other (IL-4), were noticed. After cART, earlier improvement of intracellular IL-2, interferon-gamma and IL-10 synthesis in CD4+ cells occurred compared to CD4+ counts and virus load. The usefulness of scoring the rates at which CD4+ lymphocytes are able to synthesize intracellular Th1 or Th2 cytokines, as an additional immune parameter during combined antiretroviral therapy monitoring in pediatric AIDS, is discussed.FEMS Immunology & Medical Microbiology 01/2000; 27(1):67-71. · 2.68 Impact Factor
Chapter: FIV as a Model for HIV: An Overview[Show abstract] [Hide abstract]
ABSTRACT: Animal models for human immunodeficiency virus (HIV) infection play a key role in understanding the pathogenesis of AIDS and the development of therapeutic agents and vaccines. As the only lentivirus that causes an immunodeficiency resembling that of HIV infection, in its natural host, feline immunodeficiency virus (FIV) has been a unique and powerful model for AIDS research. FIV was first described in 1987 by Niels Pedersen and co-workers as the causative agent for a fatal immunodeficiency syndrome observed in cats housed in a cattery in Petaluma, California. Since this landmark observation, multiple studies have shown that natural and experimental infection of cats with biological isolates of FIV produces an AIDS syndrome very similar in pathogenesis to that observed for human AIDS. FIV infection induces an acute viremia associated with Tcell alterations including depressed CD4 :CD8 T-cell ratios and CD4 T-cell depletion, peripheral lymphadenopathy, and neutropenia. In later stages of FIV infection, the host suffers from chronic persistent infections that are typically self-limiting in an immunocompetent host, as well as opportunistic infections, chronic diarrhea and wasting, blood dyscracias, significant CD4 T-cell depletion, neurologic disorders, and B-cell lymphomas. Importantly, chronic FIV infection induces a progressive lymphoid and CD4 T-cell depletion in the infected cat. The primary mode of natural FIV transmission appears to be blood-borne facilitated by fighting and biting. However, experimental infection through transmucosal routes (rectal and vaginal mucosa and perinatal) have been well documented for specific FIV isolates. Accordingly, FIV disease pathogenesis exhibits striking similarities to that described for HIV-1 infection.04/2007: pages 149-237;
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ABSTRACT: Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis in vivo unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that chronic HIV-replication in non-endothelial cells may produce novel factors that provoke angiogenic pathways. Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth in vitro over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses. By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development. Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10-4 to 10-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has suppressed VEGF/VEGFR-PTK expression and promoted VEGFR-independent pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies in vivo would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel VEGF-independent angiogenic pathways.Journal of Translational Medicine 09/2009; 7:75. · 3.46 Impact Factor